Treating Oxidative Stress and the Metabolic Pathology of Autism

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Little Rock,
Arkansas72202

Purpose:

Hypothesis: Many children with autism have impaired methylation and
antioxidant/detoxification capacity and chronic oxidative stress. A targeted nutritional
intervention that is designed to correct the metabolic imbalance will normalize their
metabolic profile and improve measures of autistic behavior.

Study summary:

Hypothesis and Specific Aims Hypothesis: A significant proportion of autistic children have
impaired methylation and antioxidant/detoxification capacity resulting in chronic oxidative
stress. Targeted nutritional intervention that is designed to correct the metabolic
imbalance will significantly improve their metabolic profile and improve measures of
autistic behavior.
If proven correct, this hypothesis could generate specific biomarkers to define individual
behavioral phenotypes within the autism spectrum and indicate targeted treatment options to
reduce and possibly prevent the clinical and behavioral manifestations of autism.
Specific Aim 1. To screen children with a diagnosis of autism for evidence of impaired
methylation (↓SAM/SAH) and impaired antioxidant capacity (↓GSH/GSSG)
Specific Aim 2. Children who exhibit evidence of impaired methylation and antioxidant
capacity will be randomized into a double blind placebo-controlled parallel group trial of
targeted nutritional intervention designed to correct metabolic deficiencies and imbalance
and to improve scores on standardized behavioral evaluation tests.
The two specific aims (Study Phase 1 and 2 respectively) are designed to increase the
understanding of the metabolic factors that contribute to development and clinical
manifestations of autism. We anticipate that the knowledge gained from the successful
achievement of our aims will provide an important new metabolic dimension to early diagnosis
and clinical management of autistic children.
Rationale:
Although the efficacy of nutritional intervention in autistic children has been evaluated in
numerous reports in the literature, these studies are generally considered inconclusive.
Despite positive results, most have been criticized for small sample size, poor study
design, lack of placebo group, heterogeneity of diagnosis, and/or efficacy based on
subjective parent report. Because of these limitations, none of the studies have
successfully demonstrated that targeted nutritional supplementation can be an efficacious
treatment approach for autistic children. Consequently, there is a real need for large
well-designed placebo-controlled studies with intervention strategies based on metabolic or
nutritional endpoints that can be followed for treatment efficacy and related to
quantitative improvements in standardized behavioral testing conducted in a blinded manner.
While knowledge of individual nutrient response efficacy is a desirable goal, the reality is
that all metabolic pathways are inextricably interwoven and interdependent such that
perturbation of one pathway will inevitably affect other pathways. This means that
addressing a deficit in one single pathway is highly likely to alter requirements and
possibly negatively affect other interdependent pathways. A broad spectrum balanced approach
to correct the observed metabolic imbalance in autistic children is the basis for the
intervention strategy proposed in the present intervention trial.
Because the efficacy for nutritional intervention in autistic children is based solely on
anecdotal evidence, a placebo-controlled double blind study is now clearly needed to
establish scientifically in a carefully designed clinical trial whether this approach has
efficacy or whether it does not. Either outcome will provide valuable information to parents
and physicians currently recommending these supplements. If the outcome indicates
therapeutic efficacy, this information will be published in the scientific literature so
that mainstream medicine is aware of this approach. If the outcome indicates a lack of
efficacy, dissemination of this information will be important to prevent needless wasting of
monetary resources.
Targeted Metabolic Therapy Abnormalities in folate, methionine and glutathione metabolism
will directly or indirectly affect phospholipid metabolism, mitochondrial energy metabolism,
detoxification/antioxidant capacity, and mineral cofactor availability. Therefore,
correction of an imbalance in folate/methionine and glutathione metabolism requires a global
and targeted nutritional intervention strategy rather than isolated single nutrient
supplementation. A nutritionally balanced diet consisting of fruits, vegetables and meat
will be encouraged. Although helpful, a diet-only approach is generally considered to be
insufficient to overcome genetically-based chronic metabolic imbalance. Further, control
over nutrient intake between individual children is impossible with diet-only intervention
and may be complicated by sensory issues and restricted dietary preferences in autistic
children. Therefore, we have designed a balanced and targeted supplementation strategy
specifically designed to support and correct observed metabolic imbalances in autistic
children.
Based on these considerations and extensive literature review, the supplements have been
selected to impact three core cellular functions that may be impaired with chronic oxidative
stress in many children with autism:
1. Decreased SAM/SAH ratio and cellular methylation capacity: the methionine synthase
reaction and SAM synthesis are redox sensitive and inactivated by low GSH and oxidative
stress. 40-43
2. Cell membrane integrity: membrane lipid peroxidation occurs with oxidative stress as
evidenced by elevated isoprostanes in autistic children.24,44,45
3. Antioxidant and detoxification support (mitochondrial and cytosolic): Glutathione
levels and redox ratio are significantly reduced in many autistic children.1,42,46
The selection of supplements and dose level was made in consultation with Bryan Jepson MD,
who recently published a book entitled "Changing the course of autism: a scientific approach
for parents and physicians" (available to IRB upon request). Dr. Jepson is a parent of an
autistic child and a physician who has treated hundreds of autistic children in his autism
practice in Austin, Texas. The supplements are highly unlikely to produce toxic side effects
based on previous published studies in the scientific literature showing efficacy in
children without toxic side effects. We have created a table (submitted and approved by the
IRB) indicating that for each micronutrient, the supplement level falls below the IOM
designated safe upper limit. The table also allows a comparison of the safe upper limit with
the study dose for each of the micronutrients and provides quotes from the scientific
literature indicating that intakes above our supplement levels have been shown to be
non-toxic. Stephen Kahler MD, clinical geneticist and member of our research team, and our
PCP consultant, Bryan Jepson MD, both agree that these levels are safe and likely to be
efficacious. Indeed, the same supplement levels are commonly prescribed by PCPs who are
currently treating thousands of autistic children without report of toxic side effects.
Finally, we consulted locally with Donald Mock, MD PhD, who also expressed confidence in the
safety of the recommended supplements and dose levels.
The selected supplements are all available over-the counter (OTC) and considered by the FDA
to be GRAS (generally recognized as safe) and fall under safety regulations of the DSHEA Act
(Dietary Supplement Health and Education Act). We have chosen to obtain the supplements from
a highly reputable compounding pharmacy, Kirkman Laboratories to avoid additives and food
dyes often present in OTC supplements that may cause negative side effects in some autistic
children. Kirkman Laboratories has been manufacturing prescription drugs and nutritional
supplements since 1949 using Standard Operating Procedures required by the FDA (FDA
registration 3025062). Their manufacturing process is based on "Good Manufacturing
Practices" as defined by the FDA and is monitored by an independent quality control
department.
Our research team is strengthened by the continued participation of the ACH Research
Pharmacist, who has been working closely with Kirkman Laboratories. The ACH Research
Pharmacist will receive and distribute the supplements/placebos and will assure proper
storage conditions as he has for our open label study, Protocol #28839.
Behavioral Tests:
Each of the tests was chosen based on the recommendation of our consultant and certified
behavioral analyst, Doreen Granpesheh PhD. These tests are deemed most likely to detect
change with treatment intervention and when appropriate (e.g., ADOS) will be administered by
ACH Pediatric Psychologists. The ADOS behavior test will be videotaped. A second behavior
analyst will evaluate a random set of these video recordings to confirm inter-rater
reliability.
Autism Diagnostic Observation Schedule (ADOS) is the "gold standard" for assessing and
diagnosing autism and pervasive developmental disorder (PDD) across ages, developmental
levels, and language skills.
Vineland Adaptive Behavior Scales (VABS) provides an age-adjusted overall autism severity
score and individual scores for regressive/expressive verbal and non-verbal communication,
fine and gross motor skills, and interpersonal behavior.
The Social Responsiveness Scale (SRS) distinguishes autism spectrum conditions from other
child psychiatric conditions by identifying presence and extent of autistic social
impairment .Completed by a parent the SRS provides a clear picture of a child's social
impairments, assessing social awareness, social information processing, capacity for
reciprocal social communication, social anxiety/avoidance and autistic preoccupations and
traits.
Preschool Language Scale Fourth Edition (PLS-4) is a standardized test of auditory
comprehension and expressive communication for infants and toddlers. The auditory
comprehension subscale assesses basic vocabulary, concepts and grammatical markers in
preschool and higher-level abilities such as complex sentences, making comparisons and
inferences in older children. The expressive communication subscale asks preschoolers to
name objects, use concepts that describe objects, express quantity, use grammatical markers,
etc. It also includes word segmentation, completing analogies, and telling a short story in
sequence.
The Clinical Global Impression (CGI) is a tool used to pick up subtle behavior changes that
may not be caught by the other behavior tests. The CGI is 3 item observer rated scale that
measures illness severity, global improvement or change, and therapeutic response. This tool
is widely available to be used in the public domain. For our study, the Pediatric
Psychologists will be using the illness severity and global improvement sections of this
tool.
The Block Food Frequency Questionnaire, the Child's Sleep Habits Questionnaire, the GI
Symptom Inventory, the Pediatric Quality of Life Questionnaire (PQOL), and the Parental
Stress Index (PSI) are completed by the parent(s) with the assistance of the study nurse.
Supplement Doses, Formulation and Administration Targeted metabolic support is based on
metabolic evidence of oxidative stress and/or impaired methylation capacity. The supplements
will be in the form of methyl B12 pre-loaded syringes (previously approved by UAMS IRB
[protocol #28839] and the FDA [IND # 71459]), small capsules (folinic acid and carnitine),
powder (minerals and antioxidants), and a liquid (cod liver oil and essential fatty acids).
The placebos (cellulose) will be prepared in identical form by Kirkman Laboratories. The
Methyl B12 pre-loaded syringes and placebos will be prepared in identical form by Custom
Compounding Pharmacy
The rationale and dosing schedule for each supplement is based on its established efficacy
in the following categories:
1. For SAM/SAH and methylation capacity:
Injectible methylB12; Folinic acid.
2. Mineral cofactors for enzymes involved in methylation and transsulfuration:
Magnesium citrate47,48 ; Selenium 49,51, Zinc picolinate50,51, Molybdenum51; Calcium
citrate51; Vitamin D 52.
3. For Antioxidant and detoxification support (cytosolic and mitochondrial):
Multivitamin powder containing: Vitamin C 52; Vitamin E 52,53; Vitamin K 52 ; B-Complex
52: B-1; B-2 52; B-3 52; B-6 52, Pantothenic Acid 52; Biotin 52; pyridoxal 52, Taurine
54 ; Pycnogenol 55,56,57; CoQ 10 58; Choline 52.
4. For Membrane integrity: Cod Liver Oil plus essential fatty acids 53, Acetyl L-Carnitine
59,60